CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 202293Orig1s000 RISK ASSESSMENT and RISK MITIGATION REVIEW(S) Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research Office of Surveillance and Epidemiology Office of Medication Error Prevention and Risk Management Final Risk Evaluation and Mitigation Strategy (REMS) Review Date: December 20, 2013 Reviewer(s): Amarilys Vega, M.D., M.P.H, Medical Officer Division of Risk Management (DRISK) Team Leader: Cynthia LaCivita, Pharm.D., Team Leader DRISK Drug Name(s): Dapagliflozin Therapeutic Class: Antihyperglycemic, SGLT2 Inhibitor Dosage and Route: 5 mg or 10 mg, oral tablet Application Type/Number: NDA 202293 Submission Number: Original, July 11, 2013; Sequence Number 0095 Applicant/sponsor: Bristol-Myers Squibb and AstraZeneca OSE RCM #: 2013-1639 and 2013-1637 *** This document contains proprietary and confidential information that should not be released to the public. *** Reference ID: 3426343 1 INTRODUCTION This review documents DRISK’s evaluation of the need for a risk evaluation and mitigation strategy (REMS) for dapagliflozin (NDA 202293). The proposed proprietary name is Forxiga. Bristol-Myers Squibb and AstraZeneca (BMS/AZ) are seeking approval for dapagliflozin as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). Bristol-Myers Squibb and AstraZeneca did not submit a REMS or risk management plan (RMP) with this application. At the time this review was completed, FDA’s review of this application was still ongoing. 1.1 BACKGROUND Dapagliflozin. Dapagliflozin is a potent, selective, and reversible inhibitor of the human renal sodium glucose cotransporter 2 (SGLT2), the major transporter responsible for renal glucose reabsorption. Dapagliflozin lowers plasma glucose by inhibiting the renal reabsorption of glucose, and by promoting its urinary excretion. Dapagliflozin’s initial application, submitted December 28, 2010, demonstrated dapagliflozin’s efficacy in improving glycemic control in adults (with normal or mildly impaired renal function) with T2DM; however, it received a Complete Response (CR) letter dated January 17, 2012 due to safety concerns regarding a potential association between dapagliflozin and the risks of bladder cancer and hepatotoxicity.1 There was an imbalance in cases of breast cancer (dapagliflozin 10 vs. 3 comparator) that raised some concerns but not as serious as the signal detected for bladder cancer. In addition, the Division of Metabolism and Endocrinology Products (DMEP) determined that additional data was necessary to confirm neutral Hazard Ratio (HR) for cardiovascular events (CV). The CR letter did not include a request for a REMS. Dapagliflozin was approved by the European Commission on November 14, 2012 for the treatment of T2DM and is also approved and marketed in Australia (Oct-2012), Mexico (Mar-2013), New Zealand (June-2013), Brazil (July-2013), and Argentina (Sep-2013). On July 11, 2013, BMS/AZ resubmitted their application for dapagliflozin including a response to the CR letter. The recommended dose is 5 mg or 10 mg film-coated tablet taken once daily at any time of the day regardless of meals. Other SGLT2 inhibitors. Currently, canagliflozin (Invokana®) is the only FDA-approved SGLT2 inhibitor (approved on March 29, 2013). Canagliflozin is contraindicated in patients with severe renal impairment (eGFR < 30mL/min/1.73m2), end-stage renal disease or patients on dialysis. Key safety concerns listed in the Warnings and Precautions sections of the canagliflozin label include the following: • Hypotension • Impairment of renal function • Hyperkalemia • Hypoglycemia (with concomitant use of insulin and insulin secretagogues) • Genital mycotic infections 1 Complete Response Letter, dated January 17, 2012. Reference ID: 3426343 • Hypersensitivity reactions • Increased in LDL-cholesterol Canagliflozin was approved without a REMS; product label includes a Medication Guide. Other SGLT2 inhibitors under clinical development include empagliflozin, ipragliflozin, togogliflozin and luseogliflozin.2,3 See Appendix for a side-by-side comparison of canagliflozin and dapagliflozin. 1.2 REGULATORY HISTORY Following is dapagliflozin’s regulatory history, in pertinent part: • December 28, 2010 – BMS submits a new application for dapagliflozin containing a proposed Risk Management Plan (RMP) based on the European Union (EU) format. • July 19, 2011 – Advisory Committee meeting for dapagliflozin. The committee voted against dapagliflozin approval due to concerns about its safety (No-9, Yes-6), in particular the potential risks of bladder and breast cancer and of hepatotoxicity. The panel recommended obtaining additional information regarding these risks. • January 17, 2012: FDA issues a Complete Response Letter due to the potential risks of bladder cancer and hepatotoxicity. • July 11, 2013: BMS/AZ resubmits dapagliflozin NDA 202293; this application did not include a REMS or an RMP. • December 12, 2013: Advisory Committee meeting for dapagliflozin (see section 4 below). • January 11, 2014: PDUFA goal date. 2 MATERIALS REVIEWED • FDA Complete Response Letter, dated January 17, 2012 • Reviewers’ Guide, dated July 2013 • Response to Complete Response Letter: New Drug Application (NDA) Resubmission, dated June 24, 2013 • December 12, 2013 Advisory Committee Meeting FDA and Applicant’s briefing document and slides. • DRISK reviews: Amarilys Vega, MD, MPH, reviews dated September 8 and November 23, 2011. 2 Kurosaki E, Ogasawara H.: Ipragliflozin and other sodium-glucose cotransporter-2 (SGLT2) inhibitors in the treatment of type 2 diabetes: preclinical and clinical data. Pharmacol Ther. 2013 Jul; 139(1):51-9. 3 Empagliflozin, (b) (4) was submitted for FDA review on March 5, 2013. At the time of this review this application was still undergoing FDA evaluation. 2 Reference ID: 3426343 3 RESULTS OF REVIEW The efficacy of dapagliflozin as monotherapy or in combination with other anti-diabetic agents to improve glycemic control in adults (with normal or mildly impaired renal function) with T2DM was established during the first review cycle. (See DRISK’s reviews from September 8 and November 23, 2011 for additional details about dapagliflozin’s clinical development program.) The second review cycle included data from 9 new Phase 2b and 3 clinical studies along with long term data from previously submitted studies for a total of 24 studies. These data provided a greater than 50% increase in patient-years exposure since the initial NDA. Also included in this safety update are some data from 2 additional studies: a pilot study in type 1 diabetes and a study of twice daily dosing. To address the hypothesis that dapagliflozin may confer cardiovascular benefit, the Applicant initiated on April 2013 the ‘Dapagliflozin Effect on Cardiovascular Events’ (DECLARE) outcomes study. DECLARE is a randomized prospective clinical outcomes study that will provide up to 6 years of exposure to dapagliflozin. Regarding dapagliflozin’s efficacy and safety based on the data included in the July 2013 resubmission, FDA’s reviewers reached to the following conclusions:4 • Efficacy – HbA1c reductions are modest but consistent across trials and similar to other recently approved antidiabetic drugs – efficacy limited to patients with normal renal function or mild renal insufficiency. – Dapagliflozin produces modest reductions in weight and systolic blood pressure. • Safety – Numeric imbalance in cases of bladder cancer not favoring dapagliflozin remains. – A potential case of drug-induced liver injury (DILI) appears to be due to autoimmune hepatitis, but an association with dapagliflozin remains plausible. – Marked liver laboratory abnormalities remain similar between treatment arms. – SGLT2 inhibitors are associated with increased LDL-C, genital infections, urinary tract infections, renal impairment, and volume depletion. – Unknown risk for fractures with long-term use in vulnerable patient populations. 4 Frank Pucino, Pharm.D, MPH, Clinical Reviewer, Division of Metabolism and Endocrinology Products, December 12, 2013 Advisory Committee meeting slide presentation. 3 Reference ID: 3426343 4 ADVISORY COMMITTEE MEETING DECEMBER 12, 2013 Panel members’ voted on the following two questions: • In accordance with FDA’s Guidance for Industry titled “Diabetes Mellitus – Evaluating Cardiovascular Risk in New Anti-diabetic Therapies to Treat Type 2 Diabetes”, has the Applicant provided sufficient evidence that dapagliflozin, relative to comparators, has an acceptable cardiovascular risk profile? Yes - 10 N0 - 4 • Based on the information included in the briefing materials and presentations today, do the benefits of dapagliflozin use outweigh identified risks and support marketing of dapagliflozin as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus? Yes - 13 N0 – 1 The Advisory Committee panel recommended that, in addition to the conduct and completion of DECLARE to assess the cardiovascular safety of dapagliflozin, the Applicant and FDA must develop a postmarketing assessment plan for the potential risks of bladder cancer and hepatotoxicity. Although the most recently submitted safety data assuaged concerns about breast cancer, a panel member recommended close monitoring of the incidence of breast cancer among dapagliflozin users because the relatively high incidence of breast cancer in the general population